It is increasingly accepted that certain cytokines may promote tumor growth and metastasis either by directly increasing cancer cell survival and invasion or by recruiting tumor-promoting inflammatory cells. Local irradiation is associated with increased cytokine production and with infiltration of inflammatory cells in tumors. Thus, these mechanisms may be more broadly relevant for tumor escape from therapy. This concept is strongly supported by results from models of tumor relapse after radiotherapy, and may be directly related to upregulation of stromal-derived factor 1 alpha (SDF11, also known as CXCL12) after local irradiation. Here, we propose to study the role of the SDF11 receptors CXCR4 and CXCR7 in local relapse and metastasis in a model of locally advanced prostate cancer recurrence after radiation therapy. In Specific Aim 1, we will examine the impact on prostate cancer cell viability and migration of (i) inhibiting CXCR4 or CXCR7 in PCa cells after irradiation; and (ii) co-culturing the irradiated prostate cancer cells with non-irradiated bone marrow-derived cells (BMDCs). In Specific Aim 2, we will evaluate (i) the impact of CXCR4 or CXCR7 inhibition in prostate cancer cells on tumor relapse after irradiation in vivo; and (ii) the role of SDF11/CXCR4 pathway in bone marrow-derived cell (BMDC) recruitment after irradiation, and the contribution of BMDCs to the vasculature of tumors after radiotherapy. In Specific Aim 3, we will test the efficacy of pharmacologic agents targeting CXCR4 or SDF11 with radiation therapy in orthotopic prostate cancer models. This proposal will uncover mechanisms of resistance to standard treatment (radiotherapy) in prostate cancer by revealing the role of SDF11 pathway and myeloid BMDC incorporation during prostate cancer relapse. Having established (i) relevant preclinical methodology to model prostate cancer in mice and measure the proposed parameters, and (ii) the necessary expertise on prostate cancer, BMDC and SDF11 biology, we think that our team is capable to successfully complete these studies. In addition, this work may be rapidly translated in the clinic by integrating CXCR4 inhibition with clinically available agents (e.g., plerixafor) with combinatorial approaches with radiation.